Method for making intermediates useful in synthesis of retroviral protease inhibitors

ABSTRACT

A synthesis is described for intermediates which are readily amenable to the large scale preparation of hydroxyethylurea-based chiral HIV protease inhibitors. The method includes forming a diastereoselective epoxide from a chiral alpha amino aldehyde.

This application is 371 of PCT/US93/04804 filed May 24, 1993, which is acontinuation in part of patent application Ser. No. 07/886,558, filedMay 20, 1992, now U.S. Pat. No. 5,482,947, which is a continuation inpart of PCT/US91/8613, filed Nov. 18, 1991, which is a continuation inpart of U.S. Pat. No. 07/789,646, filed Nov. 14, 1991, now abandoned,which is a continuation in part of U.S. patent application Ser. No.7/615,210, filed Nov. 19, 1990, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Synthesis of many HIV protease inhibitors containing a hydroxyethylamineor hydroxyethylurea isostere include the amine opening of a keyintermediate chiral epoxide. The synthesis of the key chiral epoxiderequires a multi-step synthesis starting from L-phenylalanine andresults in a low overall yield. The diastereoselectivity of thereduction step of the intermediate amino chloromethylketone is low anduse of explosive diazomethane prevents the scale up of the method tomultikilogram productions. The present invention relates to a method ofpreparing retroviral protease inhibitors and more particularly to adiastereoselective method of forming chiral intermediates for thepreparation of urea containing hydroxyethylamine protease inhibitors.

2. Related Art

Roberts et al, Science, 248, 358 (1990), Krohn et al, J. Med, Chem. 344,3340 (1991) and German, et al, J. Med. Chem., 346, 288 (1993) havepreviously reported synthesis of protease inhibitors containing thehydroxyethylamine or hydroxyethylurea isostere which include the openingof an epoxide generated in a multi-step synthesis starting from an aminoacid. These methods also contain steps which include diazomethane andthe reduction of an amino chloromethyl ketone intermediate to an aminoalcohol prior to formation of the epoxide. The overall yield of thesesyntheses are low and the use of explosive diazomethane additionallyprevents such methods from being commercially acceptable.

Tinker et al U.S. Pat. No. 4,268,688 discloses a catalytic process forthe asymmetric hydroformylation to prepare optically active aldehydesfrom unsaturated olefins. Similarly, Reetz et al U.S. Pat. No. 4,990,669discloses the formation of optically active alpha amino aldehydesthrough the reduction of alpha amino carboxylic acids or their esterswith lithium aluminum hydride followed by oxidation of the resultingprotected beta amino alcohol by dimethyl sulfoxide/oxalyl chloride orchromium trioxide/pyridine. Alternatively, protected alpha aminocarboxylic acids or esters thereof can be reduced withdiisobutylaluminum hydride to form the protected amino aldehydes.

Reetz et al (Tet. Lett., 30, 5425 (1989) disclosed the use of sulfoniumand arsonium ylides and their reactions of protected α-amino aldehydesto form aminoalkyl epoxides. This method suffers from the use of highlytoxic arsonium compounds or the use of combination of sodium hydride anddimethyl sulfoxide which is extremely hazardous in large scale. (Sodiumhydride and DMSO are incompatible: Sax, N. I., "Dangerous Properties ofIndustrial Materials", 6th Ed., Van Nostraud Reinhold Co., 1984, p. 433.Violent explosions have been reported on the reaction of sodium hydrideand excess DMSO, "Handbook of Reactive Chemical Hazards", 3rd Ed.,Butterworths, 1985, p. 295. Matteson et al Synlett., 1991, 631 reportedthe addition of chloromethylithium or bromomethylithium to racemicaldehydes.

Tet. Letters, Vol. 27, No. 7, 1986, pages 795-798 discloses in generalthe oxidation of carbonyl compounds to epoxides or chlorohydrines usingchloro- or bromomethyllithium. The reference however is silent aboutamino aldehydes as well as optically active compounds.

SUMMARY OF THE INVENTION

Human immunodeficiency virus (HIV), the causative agent of acquiredimmunodeficiency syndrome (AIDS), encodes three enzymes, including thewell-characterized proteinase belonging to the aspartic proteinasefamily, the HIV protease. Inhibition of this enzyme is regarded as apromising approach for treating AIDS. One potential strategy forinhibitor design involves the introduction of hydroxyethylenetransition-state analogs into inhibitors. Inhibitors adapting thehydroxyethylamine or hydroxyethylurea isostere are found to be highlypotent inhibitors of HIV proteases. Despite the potential clinicalimportance of these compounds, previously there were no satisfactorysynthesis which could be readily and safely scaled up to prepare largekilogram quantities of such inhibitors needed for development andclinical studies. This invention provides an efficient synthesis ofintermediates which are readily amenable to the large scale preparationof hydroxyethylurea-based chiral HIV protease inhibitors.

Specifically, the method includes preparing a diastereoselective epoxidefrom a chiral alpha amino aldehyde.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a method of preparation of HIV proteaseinhibitor that allows the preparation of commercial quantities ofintermediates of the formula ##STR1## wherein R¹ is selected from alkyl,aryl, cycloalkyl, cycloalkylalkyl and arylalkyl, which are optionallysubstituted with a group selected from alkyl, halogen, NO², OR⁹ or SR⁹,where R⁹ represents hydrogen or alkyl; and p¹ and p² independently areselected from amine protecting groups, including but not limited to,arylalkyl, substituted arylalkyl, cycloalkenylalkyl and substitutedcycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl,aralkoxycarbonyl and silyl. Examples of arylalkyl include, but are notlimited to benzyl, ortho-methylbenzyl, trityl and benzhydryl, which canbe optionally substituted with halogen, alkyl of C₁ -C₈, alkoxy,hydroxy, nitro, alkylene, amino, alkylamino, acylamino and acyl, ortheir salts, such as phosphonium and ammonium salts. Examples of arylgroups include phenyl, naphthalenyl, indanyl, anthracenyl, durenyl,9-(9-phenylfluorenyl) and phenanthrenyl, cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals containing cycloalkyls of C₆-C₁₀. Suitable acyl groups include carbobenzoxy, t-butoxycarbonyl,isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl,tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like.

Additionally, the p¹ and/or p² protecting groups can form a heterocyclicring with the nitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, e.g., nitrophthalimidyl.The term silyl refers to a silicon atom optionally substituted by one ormore alkyl, aryl and aralkyl groups.

Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of the amine functions to provide mono-or bis-disilylamine can provide derivatives of the aminoalcohol, aminoacid, amino acid esters and amino acid amide. In the case of aminoacids, amino acid esters and amino acid amides, reduction of thecarbonyl function provides the required mono- or bis-silyl aminoalcohol.Silylation of the aminoalcohol can lead to the N,N,O-tri-silylderivative. Removal of the silyl function from the silyl ether functionis readily accomplished by treatment with, for example, a metalhydroxide or ammonium fluoride reagent, either as a discrete reactionstep or in situ during the preparation of the amino aldehyde reagent.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethylsilyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Preferably p¹, p² and R¹ are independently selected from aralkyl andsubstituted aralkyl. More preferably, each of p¹, p² and R¹ is benzyl.

Protected alpha-aminoaldehyde intermediates of the formula: ##STR2## andprotected chiral alpha-amino alcohols of the formula: ##STR3## whereinp¹, p² and R¹ are as defined above, are also described herein.

As utilized herein, the term "amino epoxide" alone or in combination,means an amino-substituted alkyl epoxide wherein the amino group can bea primary, or secondary amino group containing substituents selectedfrom hydrogen, and alkyl, aryl, aralkyl, alkenyl, alkoxycarbonyl,aralkoxycarbonyl, cycloalkenyl, silyl, cycloalkylalkenyl radicals andthe like and the epoxide can be alpha to the amine. The term "aminoaldehyde" alone or in combination, means an amino-substituted alkylaldehyde wherein the amino group can be a primary, or secondary aminogroup containing substituents selected from hydrogen, and alkyl, aryl,aralkyl, alkenyl, aralkoxycarbonyl, alkoxycarbonyl, cycloalkenyl, silyl,cycloalkylalkenyl radicals and the like and the aldehyde can be alpha tothe amine. The term "alkyl", alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10, preferably from 1 to about 8, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Theterm "alkenyl", alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 18 carbon atoms preferably from 2 to about 8carbon atoms. Examples of suitable alkenyl radicals include ethenyl,propenyl, allyl, 1,4-butadienyl and the like. The term "alkoxy", aloneor in combination, means an alkyl ether radical wherein the term alkylis as defined above. Examples of suitable alkyl ether radicals includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like. The term "cycloalkenyl", alone orin combination, means an alkyl radical which contains from about 3 toabout 8 carbon atoms and is cyclic and which contains at least onedouble bond in the ring which is non-aromatic in character. The term"cycloalkenylalkyl" means cycloalkenyl radical as defined above which isattached to an alkyl radical, the cyclic portion containing from 3 toabout 8, preferably from 3 to about 6, carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like. Examples of such cycloalkenyl radicals includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, dihydrophenyland the like. The term "aryl", alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a pendent manner or may be fused.Examples of "aryl" include phenyl or naphthyl radical either of whichoptionally carries one or more substituents selected from alkyl, alkoxy,halogen, hydroxy, amino, nitro and the like, as well as p-tolyl,4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl,4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like. The term"aralkyl", alone or in combination, means an alkyl radical as definedabove in which one hydrogen atom is replaced by an aryl radical asdefined above, such as benzyl, 2-phenylethyl and the like. Examples ofsubstituted aralkyl include 3,5-dimethoxybenzyl bromide,3,4-dimethoxybenzyl bromide, 2,4-dimethoxybenzyl bromide,3,4,5-trimethoxybenzyl bromide, 4-nitrobenzyl iodide, 2,6-dichlorobenzylbromide, 1,4-bis(chloromethyl)benzene, 1,2-bis(bromomethyl)benzene,1,3-bis(chloromethyl)benzene, 4-chlorobenzyl chloride, 3-chlorobenzylchloride, 1,2-bis(chloromethyl)benzene, 6-chloropiperonyl chloride,2-chlorobenzyl chloride, 4-chloro-2-nitrobenzyl chloride,2-chloro-6-fluorobenzyl chloride,1,2-bis(chloromethyl)-4,5-dimethylbenzene, 3,6-bis(chloromethyl)durene,9,10-bis(chloromethyl)anthracene, 2,5-bis(chloromethyl)-p-xylene,2,5-bis(chloromethyl)-1,4-dimethoxybenzene,2,4-bis(chloromethyl)anisole, 4,6-(dichloromethyl)-m-xylene,2,4-bis(chloromethyl)mesitylene,4-(bromomethyl)3,5-dichlorobenzophenone,n-(alpha-chloro-o-tolyl)benzylamine hydrochloride,3-(chloromethyl)benzoyl chloride, 2-chloro-4-chloromethyltoluene,3,4-dichlorobenzyl bromide, 6-chloro-8-chloromethylbenzo-1,3-dioxan, 4-(2,6-dichlorobenzylsulphonyl)benzylbromide,5-(4-chloromethylphenyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole,5-(3-chloromethylphenyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole,4-(chloromethyl)benzoyl chloride, di(chloromethyl)toluene,4-chloro-3-nitrobenzyl chloride, 1-(dimethylchlorosilyl)-2- (p,m-chloromethylphenyl)ethane, 1-(dimethylchlorosilyl)-2- (p,m-chloromethylphenyl)ethane, 3-chloro-4-methoxybenzyl chloride,2,6-bis(chloromethyl)-4-methylphenol, 2,6-bis(chloromethyl)-p-tolylacetate, 4-bromobenzyl bromide, p-bromobenzoyl bromide, alphaalpha'-dibromo-m-xylene, 3-bromobenzyl bromide, 2-bromobenzyl bromide,1,8-bis(bromomethyl)naphthalene, o-xylylene dibromide, p-xylylenedibromide, 2,2'-bis(bromomethyl)-1,1'-biphenyl, alpha,alpha'-dibromo-2,5-dimethoxy-p-xylene, benzyl chloride, benzyl bromide,4,5-bis(bromomethyl)phenanthrene,3-(bromomethyl)benzyltriphenylphosphonium bromide,4-(bromomethyl)benzyltriphenylphosphonium bromide,2-(bromomethyl)benzyltriphenylphosphonium bromide, 1-(2-bromoethyl)-2-(bromomethyl)-4-nitrobenzene, 2-bromo-5-fluorobenzylbromide,2,6-bis(bromomethyl) fluorobenzene, o-bromomethylbenzoyl bromide,p-bromomethyl benzoyl bromide, 1-bromo-2-(bromomethyl)naphthalene,2-bromo-5-methoxybenzyl bromide, 2,4-dichlorobenzyl chloride,3,4-dichlorobenzyl chloride, 2,6-dichlorobenzyl chloride,2,3-dichlorobenzyl chloride, 2,5-dichlorobenzyl chloride,methyldichlorosilyl(chloromethylphenyl)ethane,methyldichlorosilyl(chloromethylphenyl)ethane,methyldichlorosilyl(chloromethylphenyl)ethane, 3,5-dichlorobenzylchloride, 3,5-dibromo-2-hydroxybenzyl bromide, 3,5-dibromobenzylbromide, p-(chloromethyl)phenyltrichlorosilane,1-trichlorosilyl-2-(p,m-chloromethylphenyl)ethane,1-trichlorosilyl-2-(p,m-chloromethylphenyl)ethane,1,2,4,5-tetrakis(bromomethyl)benzene. The term aralkoxycarbonyl means anaralkoxyl group attached to a carbonyl. Carbobenzoxy is an example ofaralkoxycarbonyl. The term "heterocyclic ring system" means a saturatedor partially unsaturated monocyclic, bicyclic or tricyclic heterocyclewhich contains one or more hetero atoms as ring atoms, selected fromnitrogen, oxygen, silicon and sulphur, which is optionally substitutedon one or more carbon atoms by halogen, alkyl, alkoxy, oxo, and thelike, and/or on a secondary nitrogen atom (i.e., --NH--) by alkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e. =N--) by oxido and which is attached via a carbonatom. Examples of such heterocyclic groups are pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl,phthalimide, succinimide, maleimide, and the like. Also included areheterocycles containing two silicon atoms simultaneously attached to thenitrogen and joined by carbon atoms. The term "alkylamino" alone or incombination, means an amino-substituted alkyl group wherein the aminogroup can be a primary, or secondary amino group containing substituentsselected from hydrogen, and alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like. The term "halogen" meansfluorine, chlorine, bromine or iodine. The term dihaloalkyl means twohalogen atoms, the same or different, substituted on the same carbonatom. The term "oxidizing agent" includes a single agent or a mixture ofoxidizing reagents. Examples of mixtures of oxidizing reagents includesulfur trioxidepyridine/dimethylsulfoxide, oxalyl chloride/dimethylsulfoxide, acetyl chloride/dimethyl sulfoxide, acetyl anhydride/dimethylsulfoxide, trifluoroacetyl chloride/dimethyl sulfoxide, toluenesulfonylbromide/dimethyl sulfoxide, phosphorous pentachloride/dimethyl sulfoxideand isobutylchloroformate/dimethyl sulfoxide.

A general Scheme for the preparation of amino epoxides, useful asintermediates in the synthesis of HIV protease inhibitors is shown inScheme 1 below. ##STR4##

The economical and safe large scale method of preparation of proteaseinhibitors of the present invention can alternatively utilize aminoacids or amino alcohols to form N,N-protected alpha aminoalcohol of theformula ##STR5## wherein p¹, p² and R¹ are described above.

Whether the compounds of Formula II are formed from amino acids oraminoalcohols, such compounds have the amine protected with groups p¹and p² as previously identified. The nitrogen atom can be alkylated suchas by the addition of suitable alkylating agents in an appropriatesolvent in the presence of base.

Alternate bases used in alkylation include sodium hydroxide, sodiumbicarbonate, potassium hydroxide, lithium hydroxide, potassiumcarbonate, sodium carbonate, cesium hydroxide, magnesium hydroxide,calcium hydroxide or calcium oxide, or tertiary amine bases such astriethyl amine, diisopropylethylamine, N-methylpiperidine, pyridine,dimethylaminopyridine and azabicyclononane. Reactions can be homogenousor heterogenous. Suitable solvents are water and protic solvents orsolvents miscible with water, such as methanol, ethanol, isopropylalcohol, tetrahydrofuran and the like, with or without added water.Dipolar aprotic solvents may also be used with or without added proticsolvents including water. Examples of dipolar aprotic solvents includeacetonitrile, dimethylformamide, dimethyl acetamide, acetamide,tetramethyl urea and its cyclic analog, dimethylsulfoxide,N-methylpyrrolidone, sulfolane, nitromethane and the like. Reactiontemperature can range between about -20° to 100° C. with the preferredtemperature of about 25°-85° C. The reaction may be carried out under aninert atmosphere such as nitrogen or argon, or normal or dry air, underatmospheric pressure or in a sealed reaction vessel under positivepressure. The most preferred alkylating agents are benzyl bromide orbenzyl chloride or monosubstituted aralkyl halides or polysubstitutedaralkyl halides. Sulfate or sulfonate esters are also suitable reagentsto provide the corresponding benzyl analogs and they can be preformedfrom the corresponding benzyl alcohol or formed in situ by methods wellknown to those skilled in the art. Trityl, benzhydryl, substitutedtrityl and substituted benzhydryl groups, independently, are alsoeffective amine protecting groups [p¹, p² ] as are allyl and substitutedallyl groups. Their halide derivatives can also be prepared from thecorresponding alcohols by methods well known to those skilled in the artsuch as treatment with thionyl chloride or bromide or with phosphorustri- or pentachloride, bromide or iodide or the corresponding phosphoryltrihalide. Examples of groups that can be substituted on the aryl ringinclude alkyl, alkoxy, hydroxy, nitro, halo and alkylene, amino, mono-and dialkyl amino and acyl amino, acyl and water solubilizing groupssuch as phosphonium salts and ammonium salts. The aryl ring can bederived from, for example, benzene, napthelene, indane, anthracene,9-(9-phenyl fluorenyl, durene, phenanthrene and the like. In addition,1,2-bis (substituted alkylene) aryl halides or sulfonate esters can beused to form a nitrogen containing aryl or non-aromatic heterocyclicderivative [with p¹ and p² ] or bis-heterocycles. Cycloalkylenealkyl orsubstituted cyloalkylene radicals containing 6-10 carbon atoms andalkylene radicals constitute additional acceptable class of substituentson nitrogen prepared as outlined above including, for example,cyclohexylenemethylene.

Compounds of Formula II can also be prepared by reductive alkylation by,for example, compounds and intermediates formed from the addition of analdehyde with the amine and a reducing agent, reduction of a SchiffBase, carbinolamine or enamine or reduction of an acylated aminederivative. Reducing agents include metals [platinum, palladium,palladium hydroxide, palladium on carbon, platinum oxide, rhodium andthe like] with hydrogen gas or hydrogen transfer molecules such ascyclohexene or cyclohexadiene or hydride agents such as lithiumaluminumhydride, sodium borohydride, lithium borohydride, sodiumcyanoborohydride, diisobutylaluminum hydride or lithiumtri-tert-butoxyaluminum hydride.

Additives such as sodium or potassium bromide, sodium or potassiumiodide can catalyze or accelerate the rate of amine alkylation,especially when benzyl chloride was used as the nitrogen alkylatingagent.

Phase transfer catalysis wherein the amine to be protected and thenitrogen alkylating agent are reacted with base in a solvent mixture inthe presence of a phase transfer reagent, catalyst or promoter. Themixture can consist of, for example, toluene, benzene, ethylenedichloride, cyclohexane, methylene chloride or the like with water or aaqueous solution of an organic water miscible solvent such as THF.Examples of phase transfer catalysts or reagents includetetrabutylammonium chloride or iodide or bromide, tetrabutylammoniumhydroxide, tri-butyloctylammonium chloride, dodecyltrihexylammoniumhydroxide, methyltrihexylammonium chloride and the like.

A preferred method of forming substituted amines involves the aqueousaddition of about 3 moles of organic halide to the amino acid or about 2moles to the aminoalcohol. In a more preferred method of forming aprotected amino alcohol, about 2 moles of benzylhalide in a basicaqueous solution is utilized. In an even more preferred method, thealkylation occurs at 50° C. to 80° C. with potassium carbonate in water,ethanol/water or denatured ethanol/water. In a more preferred method offorming a protected amino acid ester, about 3 moles of benzylhalide isadded to a solution containing the amino acid.

The protected amino acid ester is additionally reduced to the protectedamino alcohol in an organic solvent. Preferred reducing agents includelithium aluminiumhydride, lithium borohydride, sodium borohydride,borane, lithium tri-ter-butoxyaluminum hydride, borane. THF complex.Most preferably, the reducing agent is diisobutylaluminum hydride(DiBAL-H) in toluene. These reduction conditions provide an alternativeto a lithium aluminum hydride reduction.

Purification by chromatography is possible. In the preferredpurification method the alpha amino alcohol can be purified by an acidquench of the reaction, such as with hydrochloric acid, and theresulting salt can be filtered off as a solid and the amino alcohol canbe liberated such as by acid/base extraction.

The protected alpha amino alcohol is oxidized to form a chiral aminoaldehyde of the formula ##STR6## Acceptable oxidizing reagents include,for example, sulfur trioxide-pyridine complex and DMSO, oxalyl chlorideand DMSO, acetyl chloride or anhydride and DMSO, trifluoroacetylchloride or anhydride and DMSO, methanesulfonyl chloride and DMSO ortetrahydrothiaphene-S-oxide, toluenesulfonyl bromide and DMSO,trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutylchloroformate and DMSO. The oxidation conditions reported byReetz et al [Angew Chem., 99, p. 1186, (1987)], Angew Chem. Int. Ed.Engl., 26, p. 1141, 1987) employed oxalyl chloride and DMSO at -78° C.

The preferred oxidation method described in this invention is sulfurtrioxide pyridine complex, triethylamine and DMSO at room temperature.This system provides excellent yields of the desired chiral protectedamino aldehyde usable without the need for purification i.e., the needto purify kilograms of intermediates by chromatography is eliminated andlarge scale operations are made less hazardous. Reaction at roomtemperature also eliminated the need for the use of low temperaturereactor which makes the process more suitable for commercial production.

The reaction may be carried out under an inert atmosphere such asnitrogen or argon, or normal or dry air, under atmospheric pressure orin a sealed reaction vessel under positive pressure. Preferred is anitrogen atmosphere. Alternative amine bases include, for example,tri-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methylmorpholine, azabicyclononane, diisopropylethylamine,2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, or mixtures ofthese bases. Triethylamine is a preferred base. Alternatives to pureDMSO as solvent include mixtures of DMSO with non-protic or halogenatedsolvents such as tetrahydrofuran, ethyl acetate, toluene, xylene,dichloromethane, ethylene dichloride and the like. Dipolar aproticco-solvents include acetonitrile, dimethylformamide, dimethylacetamide,acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone,sulfolane and the like. Rather than N,N-dibenzylphenylalaninol as thealdehyde precursor, the phenylalaninol derivatives discussed above canbe used to provide the corresponding N-monosubstituted [either p¹ or p²=H] or N,N-disubstituted aldehyde.

In addition, hydride reduction of an amide or ester derivative of thecorresponding alkyl, benzyl or cycloalkenyl nitrogen protectedphenylalanine, substituted phenylalanine or cycloalkyl analog ofphenyalanine derivative can be carried out to provide a compound ofFormula III. Hydride transfer is an additional method of aldehydesynthesis under conditions where aldehyde condensations are avoided, cf,Oppenauer Oxidation.

The aldehydes of this process can also be prepared by methods ofreducing protected phenylalanine and phenylalanine analogs or theiramide or ester derivatives by, e.g., sodium amalgam with HCl in ethanolor lithium or sodium or potassium or calcium in ammonia. The reactiontemperature may be from about -20° C. to about 45° C., and preferablyfrom abut 5° C. to about 25° C. Two additional methods of obtaining thenitrogen protected aldehyde include oxidation of the correspondingalcohol with bleach in the presence of a catalytic amount of2,2,6,6-tetramethyl-1-pyridyloxy free radical. In a second method,oxidation of the alcohol to the aldehyde is accomplished by a catalyticamount of tetrapropylammonium perruthenate in the presence ofN-methylmorpholine-N-oxide.

Alternatively, an acid chloride derivative of a protected phenylalanineor phenylalanine derivative as disclosed above can be reduced withhydrogen and a catalyst such as Pd on barium carbonate or bariumsulphate, with or without an additional catalyst moderating agent suchas sulfur or a thiol (Rosenmund Reduction).

An important aspect of the present invention is a reaction involving theaddition of chloromethylithium or bromomethyllithium to the α-aminoaldehyde. Although addition of chloromethyllithium or bromomethylithiumto aldehydes is known, the addition of such species to racemic or chiralamino aldehydes to form aminoepoxides of the formula ##STR7## is novel.The addition of chloromethylithium or bromomethylithium to a chiralamino aldehyde is highly diastereoselective. Preferably, thechloromethyllithium or bromomethylithium is generated in-situ from thereaction of the dihalomethane and n-butyllithium. Acceptablemethyleneating halomethanes include chloroiodomethane,bromochloromethane, dibromomethane, diiodomethane, bromofluoromethaneand the like. The sulfonate ester of the addition product of, forexample, hydrogen bromide to formaldehyde is also a methyleneatingagent. Tetrahydrofuran is the preferred solvent, however alternativesolvents such as toluene, dimethoxyethane, ethylene dichloride,methylene chloride can be used as pure solvents or as a mixture. bipolaraprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone areuseful as solvents or as part of a solvent mixture. The reaction can becarried out under an inert atmosphere such as nitrogen or argon. Forn-butyl lithium can be substituted other organometalic reagents reagentssuch as methyllithium, tert-butyl lithium, sec-butyl lithium,phenyllithium, phenyl sodium and the like. The reaction can be carriedout at temperatures of between about -80° C. to 0° C. but preferablybetween about -80° C. to -20° C. The most preferred reactiontemperatures are between -40° C. to -15° C. Reagents can be added singlybut multiple additions are preferred in certain conditions. Thepreferred pressure of the reaction is atmospheric however a positivepressure is valuable under certain conditions such as a high humidityenvironment.

Alternative methods of conversion to the epoxides of this inventioninclude substitution of other charged methylenation precurser speciesfollowed by their treatment with base to form the analogous anion.Examples of these species include trimethylsulfoxonium tosylate ortriflate, tetramethylammonium halide, methyldiphenylsulfoxonium halidewherein halide is chloride, bromide or iodide.

The conversion of the aldehydes of this invention into their epoxidederivative can also be carried out in multiple steps. For example, theaddition of the anion of thioanisole prepared from, for example, a butylor aryl lithium reagent, to the protected aminoaldehyde, oxidation ofthe resulting protected aminosulfide alcohol with well known oxidizingagents such as hydrogen peroxide, tert-butyl hypochlorite, bleach orsodium periodate to give a sulfoxide. Alkylation of the sulfoxide with,for example, methyl iodide or bromide, methyl rosylate, methyl mesylate,methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride orthe like, in the presence of an organic or inorganic base Alternatively,the protected aminosulfide alcohol can be alkylated with, for example,the alkylating agents above, to provide sulfonium salts that aresubsequently converted into the subject epoxides with tert-amine ormineral bases.

The desired epoxides form, using most preferred conditions,diastereoselectively in ratio amounts of at least about an 85:15 ratio(S:R). The product can be purified by chromatography to give thediastereomerically and enantiomerically pure product but it is moreconveniently used directly without purification to prepare HIV proteaseinhibitors.

This process is applicable to mixtures of optical isomers as well asresolved compounds. If a particular optical isomer is desired, it can beselected by the choice of starting material, e.g., L-phenylalanine,D-phenylalanine, L-phenylalaninol, D-phenylalaninol,D-hexahydrophenylalaninol and the like, or resolution can occur atintermediate or final steps. Chiral auxiliaries such as one or twoequivilants of camphor sulfonic acid, citric acid, camphoric acid,2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the compounds of this invention. These compounds orderivatives can be crystallized or separated chromatographically usingeither a chiral or achiral column as is well known to those skilled inthe art.

A further advantage of the present process is that materials can becarried through the above steps without purification of the intermediateproducts. However, if purification is desired, the intermediatesdisclosed can be prepared and stored in a pure state.

The practical and efficient synthesis described here has beensuccessfully scaled up to prepare large quantity of intermediates forthe preparation of HIV protease inhibitors. It offers several advantagesfor multikilogram preparations: (1) it does not require the use ofhazardous reagents such as diazomethane, (2) it requires no purificationby chromatography, (3) it is short and efficient, (4) it utilizesinexpensive and readily available commercial reagents, (5) it producesenantiomerically pure alpha amino epoxides. In particular, the processof the invention produces enantiomerically-pure epoxide as required forthe preparation of enantiomerically-pure intermediate for furthersynthesis of HIV protease inhibitors.

The amino epoxides were prepared utilizing the following procedure asdisclosed in Scheme II below. ##STR8##

In Scheme II, there is shown a synthesis for the epoxide, chiral N,N,α-S-tris(phenylmethyl)-2S-oxiranemethan-amine. The synthesis startsfrom L-phenylalanine. The aldehyde is prepared in three steps fromL-phenylalanine or phenylalinol. L-Phenylalanine is converted to theN,N-dibenzylamino acid benzyl ester using benzyl bromide under aqueousconditions. The reduction of benzyl ester is carried out usingdiisobutylaluminum hydride (DIBAL-H) in toluene. Instead of purificationby chromatography, the product is purified by an acid (hydrochloricacid) quench of the reaction, the hydrochloride salt is filtered off asa white solid and then liberated by an acid/base extraction. After onerecrystallization, chemically and optically pure alcohol is obtained.Alternately, and preferably, the alcohol can be obtained in one step in88% yield by the benzylation of L-phenylalaninol using benzylbromideunder aqueous conditions. The oxidation of alcohol to aldehyde is alsomodified to allow for more convenient operation during scaleup. Insteadof the standard Swern procedures using oxalyl chloride and DMSO inmethylene chloride at low temperatures (very exothermic reaction),sulfur trioxide-pyridine/DMSO was employed (Parikh, J., Doering, W., J.Am. Chem. Soc., 89, p. 5505, 1967) which can be conveniently performedat room temperature to give excellent yields of the desired aldehydewith high chemical and enantiomer purity which does not requirepurification.

An important reaction involves the addition of chloromethylithium orbromomethylithium to the aldehyde. Although addition ofchloromethyllithium or bromomethylithium to aldehydes has been reportedpreviously, the addition of such species to chiral α-amino aldehydes toform chiral-aminoepoxides is believed to be novel. Now,chloromethyllithium or bromomethylithium is generated in-situ fromchloroiodomethane(or bromochloromethane) or dibromomethane andn-butyllithium at a temperature in a range from about -78° C. to about-10° C. in THF in the presence of aldehyde. The desired chlorohydrin orbromohydrin is formed as evidenced by TLC analyses. After warming toroom temperature, the desired epoxide is formed diastereoselectively ina 85:15 ratio (S:R). The product can be purified by chromatography togive the diastereomerically pure product as a colorless oil but it ismore conveniently used directly without purification.

EXAMPLE 1 β2- [Bis(phenylmethyl)amino]benzenepropanol METHOD 1 Step 1:Benzylation of L-Phenylalanine

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 mL) was heated to 97° C. Benzyl bromide (108.5 mL, 0.605 mol) wasthen slowly added (addition time--25 min). The mixture was stirred at97° C. for 30 minutes under a nitrogen atmosphere. The solution wascooled to room temperature and extracted with toluene (2×250 mL). Thecombined organic layers were washed with water and brine, dried overmagnesium sulfate, filtered and concentrated to an oil. The identity ofthe product was confirmed as follows. Analytical TLC (10% ethylacetate/hexane, silica gel) showed major component at Rf value=0.32 tobe the desired tribenzylated compound,N,N-bis(phenylmethyl)-L-phenylalanine phenylmethyl ester. This compoundcan be purified by column chromatography (silica gel, 15% ethylacetate/hexanes). Usually the product is pure enough to be used directlyin the next step without further purification. ¹ H NMR spectrum was inagreement with published literature. ¹ H NMR (CDCL₃) ∂, 3.00 and 3.14(ABX-system, 2H, J_(AB) =14.1 Hz, J_(AX) =7.3 Hz and J_(BX) =5.9 Hz),3.54 and 3.92 (AB-System , 4 H, J_(AB) =13.9 Hz), 3.71 (t, 1H, J=7.6Hz), 5.11 and 5.23 (AB-System, 2H, J_(AB) =12.3 Hz), and 7.18 (m, 20 H).EIMS: m/z 434 (M-1).

Step 2: βS-2-[Bis(phenylmethyl)amino]benzenepropanol from the DIBALReduction of N,N-bis (phenylmethyl)-L-Phenylalanine phenylmethyl ester

The benzylated phenylalanine phenylmethyl ester (0.302 mol) from theprevious reaction was dissolved in toluene (750 mL) and cooled to -55°C. A 1.5M solution of DIBAL in toluene (443.9 mL, 0.666 mol) was addedat a rate to maintain the temperature between -55° to -50° C. (additiontime--1 hr). The mixture was stirred for 20 minutes under a nitrogenatmosphere and then quenched at -55° C. by the slow addition of methanol(37 ml). The cold solution was then poured into cold (5° C.) 1.5N HClsolution (1.8 L). The precipitated solid (approx. 138 g) was filteredoff and washed with toluene. The solid material was suspended in amixture of toluene (400 mL) and water (100 ml). The mixture was cooledto 5° C. and treated with 2.5N NaOH (186 mL) and then stirred at roomtemperature until solid dissolved. The toluene layer was separated fromthe aqueous phase and washed with water and brine, dried over magnesiumsulfate, filtered and concentrated to a volume of 75 mL (89 g). Ethylacetate (25 mL) and hexane (25 mL) were added to the residue upon whichthe desired alcohol product began to crystallize. After 30 min, anadditional 50 mL hexane were added to promote further crystallization.The solid was filtered off and washed with 50 mL hexane to give 34.9 gof first crop product. A second crop of product (5.6 g) was isolated byrefiltering the mother liquor. The two crops were combined andrecrystallized from ethyl acetate (20 mL) and hexane (30 mL) to give 40g of βS-2-[Bis(phenyl-methyl)amino] benzenepropanol, 40% yield fromL-phenylalanine. An additional 7 g (7%) of product can be obtained fromrecrystallization of the concentrated mother liquor. TLC of productRf=0.23 (10% ethyl acetate/hexane, silica gel); ¹ H NMR (CDCl₃) ∂2.44(m, 1H,), 3.09 (m, 2H), 3.33 (m, 1H), 3.48 and 3.92 (AB-System, 4H,J_(AB) =13.3 Hz), 3.52 (m, 1H) and 7.23 (m, 15H); [α]_(D) 25+42.4 (c1.45, CH₂ Cl₂); DSC 77.67° C.; Anal. Calcd. for C₂₃ H₂₅ ON: C, 83.34; H,7.60; N, 4.23. Found: C, 83.43; H, 7.59; N, 4.22. HPLC on chiralstationary phase: Cyclobond I SP column (250×4.6 mm I.D.), mobile phase:methanol/triethyl ammonium acetate buffer pH 4.2 (58:42, v/v), flow-rateof 0.5 ml/min, detection with detector at 230 nm and a temperature of 0°C. Retention time: 11.25 min., retention time of the desired productenantiomer: 12.5 min.

METHOD 2 Preparation of βS-2-[Bis(phenylmethyl)amino]benzenepropanolfrom the N,N-Dibenzylation of L-Phenylalaninol

L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution ofpotassium carbonate (484.6 g, 3.506 mol) in 710 mL of water. The mixturewas heated to 65° C. under a nitrogen atmosphere. A solution of benzylbromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added at a ratethat maintained the temperature between 60°-68° C. The biphasic solutionwas stirred at 65° C. for 55 min and then allowed to cool to 10° C. withvigorous stirring. The oily product solidified into small granules. Theproduct was diluted with 2.0 L of tap water and stirred for 5 minutes todissolve the inorganic by products. The product was isolated byfiltration under reduced pressure and washed with water until the pH is7. The crude product obtained was air dried overnite to give a semi-drysolid (407 g) which was recrystallized from 1.1 L of ethylacetate/heptane (1:10 by volume). The product was isolated by filtration(at -8° C.), washed with 1.6 L of cold (-10° C.) ethyl acetate/heptane(1:10 by volume) and air-dried to give 339 g (88% yield) ofβS-2-[Bis(phenylmethyl)amino]benzenepropanol, mp 71.5°-73.0° C. Moreproduct can be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed in Method 1.

EXAMPLE 2 METHOD 1 αS-[Bis(phenylmethyl)amino]benzenepropanaldehyde

βS-2-[Bis(phenylmethyl)amino]benzene-propanol (200 g, 0.604 mol) wasdissolved in triethylamine (300 mL, 2.15 mol). The mixture was cooled to12° C. and a solution of sulfur trioxide/pyridine complex (380 g, 2.39mol) in DMSO (1.6 L) was added at a rate to maintain the temperaturebetween 8°-17° C. (addition time -1.0 h). The solution was stirred atambient temperature under a nitrogen atmosphere for 1.5 hour at whichtime the reaction was complete by TLC analysis (33% ethylacetate/hexane, silica gel). The reaction mixture was cooled with icewater and quenced with 1.6 L of cold water (10°-15° C.) over 45 minutes.The resultant solution was extracted with ethyl acetate (2.0 L), washedwith 5% citric acid (2.0 L), and brine (2.2 L), dried over MgSO₄ (280 g)and filtered. The solvent was removed on a rotary evaporator at 35°-40°C. and then dried under vaccuum to give 198.8 g ofαS-[Bis-(phenylmethyl)amino]benzenepropanaldehyde as a pale yellow oil(99.9%). The crude product obtained was pure enough to be used directlyin the next step without purification. The analytical data of thecompound were consistent with the published literature.[α]_(D) 25=-92.9°(c 1.87, CH₂ Cl₂); ¹ H NMR (400 MHz, CDCl₃) ∂, 2.94 and 3.15(ABX-System, 2H, J_(AB) =13.9 Hz, J_(AX) =7.3 Hz and J_(BX) =6.2 Hz),3.56 (t, 1H, 7.1 Hz), 3.69 and 3.82 (AB-System, 4H, J_(AB) =13.7 Hz),7.25 (m, 15 H) and 9.72 (s, 1H); HRMS calcd for (M+1) C₂₃ H₂₄ NO330.450, found: 330.1836. Anal. Calcd. for C₂₃ H₂₃ ON: C, 83.86; H,7.04; N, 4.25. Found: C, 83.64; H, 7.42; N, 4.19. HPLC on chiralstationary phase:(S,S) Pirkle-Whelk-O 1 column (250×4.6 mm I.D.), mobilephase: hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min,detection with UV detector at 210nm. Retention time of the desiredS-isomer: 8.75 min., retention time of the R-enanatiomer 10.62 min.

METHOD 2

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) was cooled to -74° C. A solution of DMSO (12.0 ml, 0.155 mol)in dichloromethane (50 ml) was then slowly added at a rate to maintainthe temperature at -74° C. (addition time -1.25 hr). The mixture wasstirred for 5 min. followed by addition of a solution of the alcohol(0.074 mol) in 100 ml of dichloromethane (addition time -20 min., temp.-75° C. to -68° C.). The solution was stirred at -78° C. for 35 minutesunder a nitrogen atmosphere. Triethylamine (41.2 ml, 0.295 mol) was thenadded over 10 min. (temp. -78° to -68° C.) upon which the ammonium saltprecipitated. The cold mixture was stirred for 30 min. and then water(225 ml) was added. The dichloromethane layer was separated from theaqueous phase and washed with water, brine, dried over magnesiumsulfate, filtered and concentrated. The residue was diluted with ethylacetate and hexane and then filtered to further remove the ammoniumsalt. The filtrate was concentrated to give the desired aldehydeproduct. The aldehyde was carried on to the next step withoutpurification.

EXAMPLE 3 METHOD 1 N,N, αS-Tris(phenylmethyl)-2S-oxiranemethanamine

A solution of αS-[Bis(phenylmethyl)amino]benzenepropanaldehyde (191.7 g,0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) in tetrahydrofuran(1.8 L) was cooled to -30 to -35° C. (colder temperature such as -70° C.also worked well but warmer temperatures are more readily achieved inlarge scale operations) in a stainless steel reactor under a nitrogenatmosphere. A solution of n-butyllithium in hexane (1.6M, 365 mL, 0.58mol) was then added at a rate that maintained the temperature below -25°C. After addition the mixture was stirred at -30° to -35° C. for 10minutes. More additions of reagents were carried out in the followingmanner: (1) additional chloroiodomethane (17 mL) was added, followed byn-butyllithium (110 mL) at <-25° C. After addition the mixture wasstirred at -30° to -35° C. for 10 minutes. This was repeated once. (2)Additional chloroiodomethane (8.5 mL, 0.11 mol) was added, followed byn-butyllithium (55 mL, 0.088 mol) at <-25° C. After addition the mixturewas stirred at -30° to -35° C. for 10 minutes. This was repeated 5times. (3) Additional chloroiodomethane (8.5 mL, 0.11 mol) was added,followed by n-butyllithium (37 mL, 0.059 mol) at <-25° C. After additionthe mixture was stirred at -30° to -35° C. for 10 minutes. This wasrepeated once. The external cooling was stopped and the mixture warmedto ambient temp. over 4 to 16 hours when TLC (silica gel, 20% ethylacetate/hexane) indicated that the reaction was completed. The reactionmixture was cooled to 10° C. and quenched with 1452 g of 16% ammoniumchloride solution (prepared by dissolving 232 g of ammonium chloride in1220 mL of water), keeping the temperature below 23° C. The mixture wasstirred for 10 minutes and the organic and aqueous layers wereseparated. The aqueous phase was extracted with ethyl acetate (2×500mL). The ethyl acetate layer was combined with the tetrahydrofuranlayer. The combined solution was dried over magnesium sulfate (220 g),filtered and concentrated on a rotary evaporator at 65° C. The brown oilresidue was dried at 70° C. in vacuo (0.8 bar) for 1 h to give 222.8 gof crude material. (The crude product weight was >100%. Due to therelative instability of the product on silica gel, the crude product isusually used directly in the next step without purification). Thediastereomeric ratio of the crude mixture was determined by proton NMR:(2S)/(2R): 86:14. The minor and major epoxide diastereomers werecharacterized in this mixture by tlc analysis (silica gel, 10% ethylacetate/hexane), Rf=0.29 & 0.32, respectively. An analytical sample ofeach of the diastereomers was obtained by purification on silica-gelchromatography (3% ethyl acetate/hexane) and characterized as follows:

N,N, αS-Tris(phenylmethyl)-2S-oxiranemethanamine

1H NMR (400 MHz, CDCl₃) ∂2.49 and 2.51 (AB-System, 1H, J_(AB) =2.82),2.76 and 2.77 (AB-System, 1H, J_(AB) =4.03 ), 2.83 (m, 2H), 2.99 & 3.03(AB-System, 1H, J_(AB) =10.1 Hz), 3.15 (m, 1H), 3.73 & 3.84 (AB-System,4H, J_(AB) =14.00), 7.21 (m, 15H); ¹³ C NMR (400 MHz, CDCl₃) ∂139.55,129.45, 128.42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23, 52.13,45.99, 33.76; HRMS calcd for C₂₄ H₂₆ NO (M+1) 344.477, found 344.2003.

N,N, αS-Tris(phenylmethyl)-2R-oxiranemethanamine

¹ H NMR (300 MHz, CDCl₃) ∂2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m, 2H), 2.97(m, 1H), 3.14 (m, 1H), 3.85 (AB-System, 4H), 7.25 (m, 15H).HPLC onchiral stationary phase: Pirkle-Whelk-O 1 column (250×4.6 mm I.D.),mobile phase: hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min,detection with UV detector at 210 nm. Retention time of(8): 9.38 min.,retention time of enanatiomer of (4): 13.75 min.

METHOD 2

A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) was cooled to -78° C., undera nitrogen atmosphere. A 1.6M solution of n-butyllithium in hexane (25ml, 0.040 mol) was then added at a rate to maintain the temperature at-75° C. (addition time--15 min.). After the first addition, additionalchloroiodomethane (1.6 ml, 0.022 mol) was added again, followed byn-butyllithium (23 ml, 0.037 mol), keeping the temperature at -75° C.The mixture was stirred for 15 min. Each of the reagents,chloroiodomethane (0.70 ml, 0.010 mol) and n-butyllithium (5 ml, 0.008mol) were added 4 more times over 45 min. at -75° C. The cooling bathwas then removed and the solution warmed to 22° C. over 1.5 hr. Themixture was poured into 300 ml of saturated aq. ammonium chloridesolution. The tetrahydrofuran layer was separated. The aqueous phase wasextracted with ethyl acetate (1×300 ml). The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered andconcentrated to give a brown oil (27.4 g). The product could be used inthe next step without purification. The desired diastereomer can bepurified by recrystallization at a subsequent step.

The product could also be purified by chromatography.

METHOD 3

A solution of αS-[Bis(phenylmethyl)amino]benzenepropanaldehyde (178.84g, 0.54 mol) and bromochloromethane (46 mL, 0.71 mol) in tetrahydrofuran(1.8 L) was cooled to -30° to -35° C. (colder temperature such as -70°C. also worked well but warmer temperatures are more readily achieved inlarge scale operations) in a stainless steel reactor under a nitrogenatmosphere. A solution of n-butyllithium in hexane (1.6M, 340 mL, 0.54mol) was then added at a rate that maintained the temperature below -25°C. After addition the mixture was stirred at -30° to -35° C. for 10minutes. More additions of reagents were carried out in the followingmanner: (1) additional bromochloromethane (14 mL) was added, followed byn-butyllithium (102 mL) at <-25° C. After addition the mixture wasstirred at -30° to -35° C. for 10 minutes. This was repeated once. (2)Additional bromochloromethane (7 mL, 0.11 mol) was added, followed byn-butyllithium (51 mL, 0.082 mol) at <-25° C. After addition the mixturewas stirred at -30° to -35° C. for 10 minutes. This was repeated 5times. (3) Additional bromochloromethane (7 mL, 0.11 mol) was added,followed by n-butyllithium (51 mL, 0.082 mol) at <-25° C. After additionthe mixture was stirred at -30° to -35° C. for 10 minutes. This wasrepeated once. The external cooling was stopped and the mixture warmedto ambient temp. over 4 to 16 hours when TLC (silica gel, 20% ethylacetate/hexane) indicated that the reaction was completed. The reactionmixture was cooled to 10° C. and quenched with 1452 g of 16% ammoniumchloride solution (prepared by dissolving 232 g of ammonium chloride in1220 mL of water), keeping the temperature below 23° C. The mixture wasstirred for 10 minutes and the organic and aqueous layers wereseparated. The aqueous phase was extracted with ethyl acetate (2×500mL). The ethyl acetate layer was combined with the tetrahydrofuranlayer. The combined solution was dried over magnesium sulfate (220 g),filtered and concentrated on a rotary evaporator at 65° C. The brown oilresidue was dried at 70° C. in vacuo (0.8 bar) for 1 h to give 222.8 gof crude material.

From the foregoing detailed description, one skilled in the art caneasily ascertain the essential characteristics of this invention, andwithout departing from the spirit and scope thereof, can make variouschanges and modifications of the invention to adapt it to various usagesand conditions.

What is claimed is:
 1. A method of preparing an aminoepoxide compound ofFormula I: ##STR9## wherein p¹ and p² independently are selected fromacyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl andcycloalkenylalkyl;wherein further p¹ and p² may be taken together withthe nitrogen atom of Formula I to form a heterocyclic ring systemcontaining said nitrogen atom as a ring member; and wherein R¹ isselected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl,which are optionally substituted with a group selected from alkyl, halo,NO₂, OR⁹ and SR⁹, wherein R⁹ is selected from hydrogen and alkyl; andwherein any of the foregoing groups of p¹, p² and R¹ may be substitutedat one or more substitutable positions with one or more radicalsindependently selected from halo, alkyl of C₁ -C₈, alkoxy, hydroxy,nitro, alkenyl, amino, alkylamino, acylamino and acyl; or apharmaceutically-acceptable salt thereof; said method comprising thesteps of forming a protected aminoalcohol, oxidizing said protectedaminoalcohol to a chiral protected aminoaldehyde anddiastereoselectively forming the aminoepoxide from said aminoaldehydewith an organometallic methylene-adding reagent in an appropriatesolvent at a temperature above -80° C.
 2. A diastereoselective andenantio selective method of preparing a protected chiral alpha-aminoepoxide of Formula I: ##STR10## wherein p¹ and p² independently areselected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl,alkoxycarbonyl and cycloalkenylalkyl;wherein further p¹ and p² may betaken together with the nitrogen atom of Formula I to form aheterocyclic ring system containing said nitrogen atom as a ring member;and wherein R¹ is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyland aralkyl, which are optionally substituted with a group selected fromalkyl, halo, NO₂, OR⁹ and SR⁹, wherein R⁹ is selected from hydrogen andalkyl; and wherein any of the foregoing groups of p¹, p² and R¹ may besubstituted at one or more substitutable positions with one or moreradicals independently selected from halo, alkyl of C₁ -C₈, alkoxy,hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; or apharmaceutically-acceptable salt thereof; said method comprisingtreating a protected chiral aminoaldehyde substrate with anorganometallic methylene-adding reagent in an appropriate solvent at atemperature above -80° C.
 3. The method of claim 2 wherein p¹ and p²independently are selected from carbobenzoxy, t-butoxycarbonyl, acetyl,butyryl, benzoyl, isobutyloxycarbonyl, allyl,1,2-bis(dimethylsilyl)ethane, 1,2-bis(dimethylsilyl)benzene, substitutedbenzoyl, trifluoroacetyl, trichloroacetyl, phthaloyl, benzyl,ortho-methylbenzyl, trityl, 1,2-bis(methylene)benzene, benzhydryl,phenethyl, phenpropyl, phenyl, naphthalenyl, indenyl, anthracenyl,durenyl, 9-(9-phenyl-fluoroenyl) and phenanthrenyl, wherein further p¹and p² may be taken together to form with the nitrogen atom of Formula Ia radical selected from phthalimide, succinimide and maleimide, andwherein any of the foregoing groups of p¹ and p² may be substituted atone or more substitutable positions with one or more radicalsindependently selected from halo, alkyl of C₁ -C₈, alkoxy, hydroxy,nitro, alkenyl, amino, alkylamino, acylamino and acyl; or apharmaceutically-acceptable salt thereof.
 4. The method of claim 2wherein p¹ and p² are independently selected from aralkyl,1-2-bis(methylene)benzene and aralkyl substituted with one or moreradicals independently selected from halo, alkyl of C₁ -C₈, alkoxy,hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; andwherein R¹ is aralkyl; or a pharmaceutically-acceptable salt thereof. 5.The method of claim 2 wherein the organometallic methylene-addingreagent is a halomethyllithium generated in situ.
 6. The method of claim5 wherein at least an equimolar amount of organometallicmethylene-adding reagent is added to the aminoaldehyde.
 7. The method ofclaim 5 wherein the halomethyllithium is formed through the addition ofan organolithium reagent with a dihalomethane.
 8. The method of claim 7wherein the dihalomethane is selected from bromochloromethane,chloroiodomethane, dibromomethane, diiodomethane and bromofluoromethane.9. The method of claim 5 wherein the halomethyllithium is added to theamino aldehyde at a temperature in a range of about -80° C. to about 0°C.
 10. The method of claim 5 wherein the halomethyllithium is added tothe amino aldehyde at a temperature in a range of about -40° C. and -15°C.
 11. The diastereoselective method of preparing protected chiralalpha-amino epoxides of claim 2 wherein the amino aldehyde isalpha-S-[bis(phenylmethyl)amino]-benzenepropanaldehyde.
 12. A methodaccording to claim 1 characterized in that the protected chiralalpha-amino alcohol of Formula II: ##STR11## wherein p¹, p² and R¹ aredefined as indicated in claim 1 is formed by treating an amino acid withan alkylating agent to form a protected-amino acid, and forming aprotected amino-alcohol by treating said protected amino acid with areducing agent in a suitable solvent.
 13. The method of claim 12 whereinthe reducing agent is diisobutylaluminum hydride.
 14. The method ofclaim 12 wherein said amino acid is L-phenylalanine.